Circuit-level mechanisms of memory consolidation

记忆巩固的电路级机制

• 批准号: BB/S007741/1
• 负责人: David Dupret
• 金额: $ 55.38万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS007741%2F1
• 关键词: Circuit; level; mechanisms; memory; consolidation

Understanding memory is a central goal of neuroscience, with potentially far-reaching consequences for treating Alzheimer's disease and other dementias. Memory formation requires 'offline consolidation', whereby the neuronal traces representing newly-acquired experiences are selectively stabilised during sleep. Following their retrieval, consolidated memories undergo an additional process of reconsolidation that further stabilizes them for long-term expression.Damage to particular brain regions results in selective behavioural impairments. The hippocampus, for example, encodes new memories about specific events and places (episodic and spatial memories). We lack a comprehensive understanding of how new memories gain long-term expression but two distinctive patterns of hippocampal electrical activity could promote consolidation processes: sharp-wave ripples (SWRs) and 'dentate spikes'. SWRs have received much scientific attention, and disrupting SWRs impairs memory. In contrast, little is known about dentate spikes, a misleading term that refers not to the action potentials of individual dentate granule cells (DGCs) but to a large population event that recruits many DGCs. No one has ever silenced dentate spikes to determine their role in memory. Our proposed experiments will address this important gap in our knowledge, using cutting-edge technology to detect and silence dentate spikes in the mouse brain in post-learning sleep, thereby revealing their contribution to memory consolidation.Our approach will utilise sophisticated genetic approaches that can deliver light-sensitive proteins into particular neurons (e.g. DGCs). When stimulated by light, these proteins will silence or activate those neurons. We will use real-time detection of dentate spikes to trigger light-stimulation, giving us precise control over neuronal activity during sleep.We will assess the contribution of dentate spikes to two distinct forms of memory, both of which require the hippocampus. First we will investigate the effects of dentate spike silencing on associative memory, e.g. learning that cue A predicts outcome X. Ordinarily, learning simple associations does not require the hippocampus, but if the relationship is made ambiguous (e.g. such that outcome X only follows cue A on a subset of trials), the hippocampus then becomes necessary. Second, we will investigate the effects of silencing dentate spikes on non-associative memories, e.g. using the relative novelty or familiarity of mnemonic cues to guide behavioural choices. Consolidation is thought to be critical for associative but not non-associative memories. If silencing dentate spikes also affects non-associative memory, this would suggest a more general role in memory, rather than in consolidation per se. Moreover, in control conditions we will silence DGCs during sleep but NOT during dentate spikes to see whether this also affects memory consolidation.Next, we will determine the neuronal inputs driving dentate spikes. We will use a recently developed technique to selectively target neurons in the neocortex that project directly to DGCs and determine how activating or silencing those neocortical cells alters dentate spikes.Finally, we will test how inhibiting an already consolidated memory during 'reconsolidation' affects its long-term expression. We will use a special genetically-modified mouse line that can drive the expression of a light-sensitive neuronal inhibitor selectively in cells that were active during a particular learning episode. At a later time we will reactivate this memory, which places the memory in a labile state, and then determine how inhibiting dentate spikes following this reactivation affects the reconsolidation of this memory.Collectively, our experiments will make a major contribution to a comprehensive understanding of the circuit-level mechanisms underlying the long-lasting expression of memory.

了解记忆是神经科学的核心目标，对于治疗阿尔茨海默病和其他痴呆症可能产生深远的影响。记忆形成需要“离线巩固”，代表新获得的经历的神经元痕迹在睡眠期间有选择地稳定。检索后，巩固的记忆会经历一个额外的重新巩固过程，进一步稳定它们的长期表达。特定大脑区域的损伤会导致选择性行为障碍。例如，海马体编码有关特定事件和地点的新记忆（情景记忆和空间记忆）。我们对新记忆如何获得长期表达缺乏全面的了解，但海马电活动的两种独特模式可以促进巩固过程：尖波波纹（SWR）和“齿状尖峰”。 SWR 受到了科学界的广泛关注，而破坏 SWR 会损害记忆力。相比之下，人们对齿状尖峰知之甚少，这是一个误导性的术语，它不是指单个齿状颗粒细胞 (DGC) 的动作电位，而是指招募许多 DGC 的大规模群体事件。没有人能够通过抑制齿状棘突来确定它们在记忆中的作用。我们提出的实验将解决我们知识中的这一重要空白，使用尖端技术来检测和沉默学习后睡眠中小鼠大脑中的齿状尖峰，从而揭示它们对记忆巩固的贡献。我们的方法将利用复杂的遗传方法，将光敏蛋白传递到特定的神经元（例如 DGC）中。当受到光刺激时，这些蛋白质会沉默或激活这些神经元。我们将使用齿状尖峰的实时检测来触发光刺激，使我们能够精确控制睡眠期间的神经元活动。我们将评估齿状尖峰对两种不同记忆形式的贡献，这两种记忆形式都需要海马体。首先，我们将研究齿状尖峰沉默对联想记忆的影响，例如通常，学习简单的关联不需要海马体，但如果这种关系变得模糊（例如，结果 X 仅在一部分试验中遵循提示 A），则海马体就变得必要。其次，我们将研究沉默齿状尖峰对非联想记忆的影响，例如使用相对新颖或熟悉的助记线索来指导行为选择。巩固被认为对于联想记忆至关重要，但对于非联想记忆则不然。如果沉默齿状尖峰也会影响非联想记忆，这表明它在记忆中发挥更普遍的作用，而不是在巩固本身中。此外，在控制条件下，我们将在睡眠期间而不是在齿状尖峰期间使 DGC 沉默，以观察这是否也会影响记忆巩固。接下来，我们将确定驱动齿状尖峰的神经元输入。我们将使用最近开发的技术来选择性地靶向新皮质中直接投射到 DGC 的神经元，并确定激活或沉默这些新皮质细胞如何改变齿状尖峰。最后，我们将测试在“重新巩固”过程中抑制已经巩固的记忆如何影响其长期表达。我们将使用一种特殊的转基因小鼠品系，它可以选择性地在特定学习过程中活跃的细胞中驱动光敏神经元抑制剂的表达。稍后我们将重新激活该记忆，将其置于不稳定状态，然后确定重新激活后抑制齿状尖峰如何影响该记忆的重新巩固。总的来说，我们的实验将为全面理解记忆持久表达背后的电路级机制做出重大贡献。

项目成果

Memory recall involves a transient break in excitatory-inhibitory balance.

• DOI: 10.7554/elife.70071
• 发表时间: 2021-10-08
• 期刊: eLife
• 影响因子: 7.7
• 作者: Koolschijn RS;Shpektor A;Clarke WT;Ip IB;Dupret D;Emir UE;Barron HC
• 通讯作者: Barron HC

Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice.

5-HT 转运蛋白突变小鼠的辨别厌恶学习和杏仁核反应能力增强。

• DOI: 10.1038/s41398-019-0476-8
• 发表时间: 2019
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Lima J

Over and above frequency: Gamma oscillations as units of neural circuit operations.

• DOI: 10.1016/j.neuron.2023.02.026
• 发表时间: 2023-04-05
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Fernandez-Ruiz A;Sirota A;Lopes-Dos-Santos V;Dupret D
• 通讯作者: Dupret D